Recombinant factor XIII diminishes multiple organ dysfunction in rats caused by gut ischemia-reperfusion injury.
Plasma factor XIII (FXIII) is responsible for stabilization of fibrin clot at the final stage of blood coagulation. Because FXIII has also been shown to modulate inflammation and endothelial permeability, we hypothesized that FXIII diminishes multiple organ dysfunction caused by gut I/R injury. A model of superior mesenteric artery occlusion (SMAO) was used to induce gut I/R injury. Rats were subjected to 45-min SMAO or sham SMAO and treated with recombinant human FXIII A2 subunit (rFXIII) or placebo at the beginning of the reperfusion period. Lung permeability, lung and gut myeloperoxidase activity, gut histology, neutrophil respiratory burst, and microvascular blood flow in the liver and muscles were measured after a 3-h reperfusion period. The effect of activated rFXIII on transendothelial resistance of human umbilical vein endothelial cells was tested in vitro. Superior mesenteric artery occlusion-induced lung permeability as well as lung and gut myeloperoxidase activity was significantly lower in rFXIII-treated versus untreated animals. Similarly, rFXIII-treated rats had lower neutrophil respiratory burst activity and ileal mucosal injury. Rats treated with rFXIII also had higher liver microvascular blood flow compared with the placebo group. Superior mesenteric artery occlusion did not cause FXIII consumption during the study period. In vitro, activated rFXIII caused a dose-dependent increase in human umbilical vein endothelial cell monolayer resistance to thrombin-induced injury. Thus, administration of rFXIII diminishes SMAO-induced multiple organ dysfunction in rats, presumably by preservation of endothelial barrier function and the limitation of polymorphonuclear leukocyte activation.
Zaets
Sergey B
SB
Novo Nordisk US, North Brunswick, New Jersey, USA. zaets001@yahoo.com
Xu
Da-Zhong
DZ
Lu
Qi
Q
Feketova
Eleonora
E
Berezina
Tamara L
TL
Gruda
Maryann
M
Malinina
Inga V
IV
Deitch
Edwin A
EA
Olsen
Eva H N
EH
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005176:Factor XIII / Q000494:pharmacology*; D041981:Gastrointestinal Tract / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D017538:Mesenteric Artery, Superior; D008833:Microcirculation / Q000187:drug effects; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000209:etiology*; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000503:physiopathology*; D016897:Respiratory Burst / Q000187:drug effects
D011994:Recombinant Proteins; D005176:Factor XIII; D009195:Peroxidase